Nanoparticle-Based Therapies for Wound Biofilm Infection: Opportunities and Challenges

Abstract

Clinical data from human chronic wounds implicates biofilm formation with the onset of wound chronicity. Despite the development of novel antimicrobial agents, the cost and complexity of treating chronic wound infections associated with biofilms remain a serious challenge, which necessitates the development of new and alternative approaches for effective anti-biofilm treatment. Recent advancement in nanotechnology for developing a new class of nanoparticles that exhibit unique chemical and physical properties holds promise for the treatment of biofilm infections. Over the last decade, nanoparticle-based approaches against wound biofilm infection have been directed toward developing nanoparticles with intrinsic antimicrobial properties, utilizing nanoparticles for controlled antimicrobials delivery, and applying nanoparticles for antibacterial hyperthermia therapy. In addition, a strategy to functionalize nanoparticles towards enhanced penetration through the biofilm matrix has been receiving considerable interest recently by means of achieving an efficient targeting to the bacterial cells within biofilm matrix. This review summarizes and highlights the recent development of these nanoparticle-based approaches as potential therapeutics for controlling wound biofilm infection, along with current challenges that need to be overcome for their successful clinical translation.

Figure 1

Schematic on the potential mechanisms by which biofilm formation in the wound lead to the infection persistency and wound chronicity. The presence of EPS in the biofilm creates a protective environment for the residing microorganisms against antibiotics treatments and host innate immune response. A. The presence of EPS forms protective barrier for the diffusion of antimicrobials or results in inactivation of antimicrobials at the biofilm matrix. B. In addition, the formation of biofilm structures substantially diminishes the phagocytic activities of innate immune cells (neutrophils and macrophages), by not only providing a shielding mechanism from the penetration of neutrophils, but also promoting the production of leukocyte-inactivating substances, which impairs bactericidal activity of macrophages by skewing macrophage polarization towards M2-like phenotype.

Figure 2

Schematic on the mechanism of actions for various nanoparticle (NP)-based approaches for treating biofilm infections.

Figure 3

In vitro and in vivo studies on the use of magnetic nanoparticle (MNP) targeted hyperthermia against S. aureus biofilm. A. Schematic on the strategy of MNP hyperthermia treatment in a mouse model of wound S. aureus infection. B. Representative bioluminescent image of S. aureus biofilm on 96 well plate before and after alternating magnetic field (AMF) application (for 3 min at 31 kA/m field amplitude) in vitro. The extent of bacterial killing was quantified based on the level of bioluminescence quenching that directly correlates with number of live bacteria (CFUs). C. Representative bioluminescent images of S. aureus in a mouse skin wound in vivo. Mice were infected with S. aureus (SA, 1 × 10⁷ CFU) at wound sites and MNP-anti-S. aureus antibody (MNP-anti-SA mAb) conjugates were locally injected into wound at day 2 post-infection. Then, an AMF was applied for 3 min (31 kA/m field amplitude) for four experimental groups: (1) mice injected with MNP-anti-SA mAb conjugate but without AMF treatment, (2) mice injected with MNP only and with AMF treatment, (3) mice injected with MNP-IgG conjugate and with AMF treatment, (4) mice injected with MNP-anti-SA mAb conjugate and with AMF treatment. Reprinted with permission from reference [121].